Morpholines

ABSTRACT

Morpholine derivatives of the formula ##STR1## and their acid addition salts, wherein n represents 1, 2 or 3, R 4  is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cyclo(lower)alkylmethyl, R 2  and R 3  are each hydrogen or alkyl of 1 to 10 carbon atoms and OR 5  is hydroxy, acyloxy or a protected hydroxy group possess analgesic and/or opiate antagonistic activity or are useful as intermediates for other compounds of formula I possessing such activity.

This invention relates to morpholines, more particularly to2,3-trimethylene-, tetramethylene- or pentamethylene-morpholines, toprocesses for their preparation and to pharmaceutical compositionscontaining them.

The present invention provides novel morpholine derivatives of thegeneral formula (I) ##STR2## and their acid addition salts, particularlypharmaceutically acceptable acid addition salts. In this formula nrepresents 1,2 or 3, R⁴ is hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl orcyclo(lower)alkylmethyl, R² and R³ are each hydrogen or alkyl of 1 to 10carbon atoms and OR⁵ is hydroxy, acyloxy or a protected hydroxy group.

When R² and/or R³ is an alkyl group it is preferably a lower alkylgroup. The term "lower" as used herein means that the radical referredto contains 1 to 6 carbon atoms. The radical preferably contains 1 to 4carbon atoms. For example when R², R³ or R⁴ is a lower alkyl radical,the radical may be, e.g. methyl, ethyl, propyl or butyl. When R⁴ islower alkenyl or lower alkynyl suitable groups include, for example,allyl, 2-methyl-2-propenyl, 3-methylbut-2-enyl and propynyl. When R⁴ isaryl(lower)-alkyl the group can be, for example, benzyl or phenethyl (inwhich the phenyl ring may be substituted by one or more substituentssuch as lower alkyl, lower alkoxy, amino and halogen). When R⁴ iscyclo(lower)alkylmethyl the group is preferably cyclopropylmethyl orcyclobutylmethyl. Preferably R⁴ is lower alkyl. When --OR⁵ is acyloxythe acyl group is preferably a lower alkanoyl group such as acetyl,propionyl or butyryl. When --OR⁵ is protected hydroxy suitable groupsinclude alkoxy (such as lower alkoxy e.g. methoxy, ethoxy, propyloxy,butyloxy particularly t-butyloxy), benzyloxy and (lower)alkoxymethoxy(e.g. methoxymethoxy) OR⁵ is preferably hydroxy.

n is preferably 2 i.e. the preferred compounds of the invention aretetramethylenemorpholines (an alternative name for these beingoctahydro-2H-1,4-benzoxazines) of the general formula ##STR3## [whereR², R³, R⁴ and OR⁵ are as defined above] and their acid addition salts.

The compounds of the invention may be prepared by reduction of a lactamof general formula (II) ##STR4## where n, R² and R³ have the meaningsgiven above and, if desired, converting a free base of general formula(I) into an acid addition salt thereof. The reduction may be carried outby, for example, a hydride transfer agent (e.g. lithium aluminiumhydride). In certain instances more than one reducing agent may berequired. For example reduction of a compound of general formula (II) inwhich at least one of R² and R³ is hydrogen with lithium aluminiumhydride can give some product containing a double bond in the2,3-position of the oxazine ring and this compound may be then reducedby catalytic hydrogenation.

Once a compound of general formula (I) has been prepared it may beconverted into another compound of general formula (I) by methods knownper se. For example, a compound in which R⁴ is lower alkyl, loweralkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl orcycloalkylmethyl may be prepared by "N-alkylating" a compound in whichR⁴ is hydrogen. By "N-alkylating" is meant introducing on to thenitrogen atom of the morpholine ring a lower alkyl, lower alkenyl, loweralkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cycloalkylmethylradical. In one method of carrying out the "N-alkylating" process acompound of general formula I in which R⁴ is hydrogen is reacted with ahalide of general formula

    R.sup.4' --Hal

where R^(4') is lower alkyl, lower alkenyl, lower alkynyl,aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cyclo(lower)alkylmethyl(or, is reacted with for example, a corresponding tosylate or mesylate)in the presence of an acid acceptor such as alkali metal carbonate (e.g.potassium carbonate), preferably in solution in an organic solvent.

Alternatively the compound of general formula (I) in which R⁴ ishydrogen may be alkylated by reductive alkylation i.e. by treatment withan aldehyde and hydrogen in presence of a hydrogenation catalyst. Apreferred method of cycloalkyl-methylating involves reacting theN-unsubstituted compound with a cycloalkylcarbonyl chloride to give anintermediate N-carbonyl compound which may be reduced with, for example,a hydride transfer agent.

A compound of general formula (I) in which OR⁵ is hydroxy can beobtained by removing the protecting group from a compound in which OR⁵is a protected hydroxy group. For example the ether group in a compoundin which R⁵ is lower alkyl, lower alkoxymethyl or benzyl may be removedin known manner, e.g. by treating the lower alkyl or benzyl ether withhydrogen bromide or boron tribromide, by treating the lower alkyl etherwith diisobutylaluminium hydride or by subjecting the benzyl ether tohydrogenolysis or by treating the (lower) alkoxymethyl or t-butyl etherwith dilute acid. Similarly a compound of general formula (I) in whichR⁴ is benzyl may be hydrogenolysed to a compound of general formula (I)in which R⁴ is hydrogen which, if desired may then be "alkylated" ashereinbefore described. Compounds in which R⁴ is lower alkyl,particularly methyl may also be dealkylated to compounds in which R⁴ ishydrogen, e.g. by reaction with ethyl-, phenyl-, vinyl- or2,2,2-trichloroethyl-chloroformate followed by removal of the resultingN-substituent with, for example, dilute acid or zinc and acetic acid orbasic conditions as appropriate.

A compound of general formula (I) in which OR⁵ is hydroxy can beacylated (e.g. with acetic anhydride) to give a corresponding compoundin which OR⁵ is an acyloxy group such as a lower alkanoyloxy radical.

Two or more of the above mentioned processes for interconverting thecompounds of general formula (I) may, if desired, be carried outconsecutively. In some instances it may be necessary to protect one ormore of the functional groups on the molecule while reaction occurs atanother functional group and then subsequently remove the protectinggroup or groups.

Lactams of general formula (II) may be prepared by cyclisation of anamide of general formula ##STR5## where n, R² and R⁴ are as definedabove, X is bromo or chloro, and --OR⁶ is a protected hydroxy group and,if required, alkylating the product. The cyclisation may be carried outwith a basic agent such as an alkali metal hydride or alkali metalhydroxide. Where a lactam of formula (II) is desired in which R³ isalkyl the corresponding lactam in which R³ is hydrogen may be alkylated.The alkylation may be carried out, for example, with an alkyl halide inpresence of a strong base such as sodamide, lithium diisopropylamide,lithium tetramethylpiperidide, bromomagnesium diisopropylamide orN-tertiarybutylcyclohexylamide.

If desired, the --OR⁵ protected hydroxy group in the lactam of formula(II) may be deprotected to give a lactam where --OR⁵ is hydroxy. In thiscase the protecting group and the method of deprotection are chosen, forexample, from those mentioned hereinabove, so that the product is stableunder the chosen conditions.

The amides of formula (III) are preferably prepared by condensing anα-halo acid halide of general formula (IV) ##STR6## with an aminoalcohol of general formula ##STR7## In general formula (IV) and (V)n,R²,R⁴,OR⁶ and X have the meanings given above and X¹ is chloro orbromo. The condensation can be carried out in presence of a basiccondensing agent, e.g. triethylamine.

The α-halo acid halide of general formula (IV) and the amino alcohol ofgeneral formula (V) are known compounds or can be prepared by methodsknown for analogous compounds. For example, the choice of method used toprepare the amino alcohol will depend upon the stereochemistry requiredin the final product. For example aminoalcohols which are useful asintermediates for preparing final compounds (I) possessing a trans ringfusion may be prepared by the method illustrated below ##STR8## Theoxiran of formula (VI) is reacted with an amine of formula R₄ NH₂ togive the amino alcohol of formula (VII).

The aminoalcohols which are useful as intermediates for preparing finalcompounds (I) possessing a cis ring fusion may be prepared by the methodillustrated below: ##STR9## The compound of formula (VIII) may bereacted with a m-(protected hydroxy) phenyl Grignard reagent to give thecompound of formula (IX).

If in any of the processes described above the compound of the inventionis obtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid addition salt. Conversely, if theproduct of the process is a free base a pharmaceutically acceptable acidaddition salt may be obtained by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith the conventional procedures for preparing acid addition salts frombase compounds.

Examples of acid addition salts are those formed from inorganic andorganic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric,tartaric, fumaric, oxalic, maleic, citric, acetic, formic,methane-sulphonic and p-toluenesulphonic acids.

The compounds of the invention contain at least three asymmetric carbonatoms and hence can exist in more than one isomeric form. For examplethe substituents ##STR10## at the bridgehead carbon atoms may be cis ortrans to each other and also the ##STR11## substituent may be cis ortrans to the R² substituent. The various isomeric forms can be obtainedor separated by standard procedures. For example, as exemplified above,by suitable choice of starting materials products can be obtained withthe desired configuration. The products will normally be obtained asracemates of the d- and l-enantiomorphs but optical isomers may beprepared by resolving a racemic mixture by standard methods described inthe literature. The racemate may be prepared by any of the processesoutlined above. It is to be understood that the resolution may becarried out on the racemic mixture of the final desired product or itmay be carried out on a racemic precursor of the desired compoundprovided further chemical transformations do not cause racemisation.

The compounds of the invention in which OR⁵ is a protected hydroxy groupsuch as lower alkoxy are useful, as mentioned above, for preparingcompounds in which OR⁵ is hydroxy. The compounds of general formula (I)in which OR⁵ is hydroxy or acyloxy and their pharmaceutically acceptableacid addition salts possess analgesic activity and/or opiateantagonistic activity. Some compounds also possess hypotensive orantihypertensive activity. In a standard test for analgesic activity inwhich the compound is assessed for its ability to inhibitphenylbenzoquinone-induced writhing in mice (based upon the method of E.Siegmund et al., Proc. Soc. exp. Biol. Med., 1957, 95, 729-731)3-[(2R*,4aR*,8aS*)-octahydro-2,4-dimethyl-2H-benzoxazin-8a-yl]phenol and(2R*,4aR*,8aS*)-3-(2-ethyloctahydro-4-methyl-2H-1,4-benzoxazin-8a-yl)-phenol,representative compounds of the invention, exhibited ED₅₀ 's ofrespectively 0.3 and 2.7 mg/kg (subcutaneous). In a standard test foropiate antagonism based upon the antagonism of morphine-induced Straubtail in mice (Aceto et al., Brit. J. Pharmac., 1969, 36, 225-239),3-[(2R*,4aR*,8aS*)-octahydro-2,4-dimethyl-2H-benzoxazin-8a-yl]phenol and(2R*,4aS*,8aS*)-3-(2-ethyloctahydro-4-methyl-2H-1,4-benzoxazin-8a-yl)phenol,representative compounds of the invention, exhibited ED₅₀ 's ofrespectively 1.7 and 0.13 mg/kg (subcutaneous).

The invention provides a pharmaceutical composition comprising acompound of general formula (I) in which OR⁵ is hydroxy or acyloxy or apharmaceutically acceptable acid addition salt thereof in associationwith a pharmaceutically acceptable carrier. Any suitable carrier knownin the art can be used to prepare the pharmaceutical compositions. Insuch a composition, the carrier may be a solid, liquid or mixture of asolid and a liquid. Solid form compositions include powders, tablets andcapsules. A solid carrier can be one or more substances which may alsoact as flavouring agents, lubricants, solubilisers, suspending agents,binders or tablet-disintegrating agents; it can also be an encapsulatingmaterial. In powders the carrier is a finely divided solid which is inadmixture with the finely divided active ingredient. In tablets theactive ingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 to 99,preferably 10-80% of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, and cocoa butter. The term "composition"is intended to include the formulation of an active ingredient withencapsulating material as carrier to give a capsule in which the activeingredient (with or without other carriers) is surrounded by thecarrier, which is thus in association with it. Similarly cachets areincluded.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredients can be dissolvedor suspended in a pharmaceutically acceptable sterile liquid carrier,such as sterile water, sterile organic solvent or a mixture of both.Preferably a liquid carrier is one suitable for parenteral injection.Where the active ingredient is sufficiently soluble it can be dissolvedin normal saline as a carrier; if it is too insoluble for this it canoften be dissolved in a suitable organic solvent, for instance aqueouspropylene glycol or polyethylene glycol solutions. Aqueous propyleneglycol containing from 10 to 75% of the glycol by weight is generallysuitable. In other instances other compositions can be made bydispersing the finely-divided active ingredient in aqueous starch orsodium carboxymethyl cellulose solution, or in a suitable oil, forinstance arachis oil. Liquid pharmaceutical compositions which aresterile solutions or suspensions can be utilised by intra-muscular,intraperitoneal or subcutaneous injection. In many instances a compoundis orally active and can be administered orally either in liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit doses containing appropriate quantities of the active ingredients;the unit dosage forms can be packaged compositions, for example packetedpowders or vials or ampoules. The unit dosage form can be a capsule,cachet or tablet itself, or it can be the appropriate number of any ofthese in package form. The quantity of the active ingredient in a unitdose of composition may be varied or adjusted from 5 mg. or less to 500mg. or more, according to the particular need and the activity of theactive ingredient. The invention also includes the compounds in theabsence of the carrier where the compounds are in unit dosage form. Thefollowing Examples illustrate the invention.

EXAMPLE 1 (1R*,2S*)-1-(3-Methoxyphenyl)-2-methylamino-1-cyclohexanol

(a) Crude 1-(3-methoxyphenyl)cyclohexene (prepared by the method of F.Macchia et al., Tetrahedron, 1973, 29, 2183-8) (8.35 g) was dissolved indichloromethane (50 cm³) and treated dropwise, with stirring andexternal cooling to maintain the internal temperature at 15°-20°, withm-chloroperoxybenzoic acid (10 g) in dichloromethane (150 cm³) over 3/4hr. The mixture was then stirred at room temperature for 1 hr. Excessperacid was destroyed by addition of 10% sodium sulphite. The mixturewas washed with half-saturated sodium bicarbonate solution (2×50 cm³)until all solid m-chlorobenzoic acid had dissolved, and then with waterand saturated brine. The organic phase was then evaporated, leavingcrude 1-(3-methoxyphenyl)-cyclohexane-1,2-oxide as a yellow oil (10.6 g)

(b) The crude epoxide from part (a) (10.3 g) was dissolved in ethanolicmethylamine (33%; 125 cm³) and heated in a sealed vessel at 100°-110°for 24 hrs. The mixture was evaporated under reduced pressure and thedark, oily residue was dissolved in ether (50 cm³). The solution wasextracted with 2 N sulphuric acid (3×25 cm³). The combined acid extractswere back-extracted with ether (3×20 cm³) and the ether solutions werediscarded. The acid phase was made basic with potassium carbonate andthe product was extracted into dichloromethane. The combined extractswere dried (NaSO₄) and evaporated, giving a light brown solid (8.90 g).Recrystallisation from cyclohexane gave the title compound as colourlesscrystals (4.99 g) m.p. 113°-4°.

Found: C, 71.6; H, 9.1; N, 5.6 C₁₄ H₂₁ NO₂ requires C, 71.45; H, 9.0; N,5.95%.

EXAMPLE 2 (1R*,2S*)-2-(2-bromopropion-N-methylamido)-1-(3-methoxyphenyl)-1-cyclohexanol

The product of Example 1 (3.525 g) in dichloromethane (55 cm³)containing triethylamine (2.1 cm³, 1.525 g) was treated, with stirringand external cooling to maintain the internal temperature at 20°, with2-bromopropionyl bromide (3.24 g) in dichloromethane (25 cm³) over 1 hr.The mixture was kept at room temperature for a further 2 hr. and wasthen concentrated under reduced pressure to an oily solid. The solid waspartitioned between water (30 cm³) and ether (30 cm³). The ether phasewas washed with N sulphuric acid (30 cm³), saturated brine (30 cm³),dried (Na₂ SO₄) and evaporated, leaving crude title compound as a palegreen oil (5.99 g) characterised spectroscopically.

EXAMPLE 3 (2R*,4aR*,8aS*) and(2R*,4aS*,8aR*-Hexahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazin-3(4H)-one

Crude bromoamide product of Example 2 (5.45 g), was treated at roomtemperature in propan-2-ol (50 cm³) with 10 N aqueous sodium hydroxide(4.5 cm³) with stirring for 19 hr. The solvent was removed under reducedpressure and the aqueous residue was diluted with water (30 cm³) andextracted with ether (3×50 cm³). The combined extracts were dried (Na₂SO₄), evaporated and re-evaporated with toluene (50 cm³) to removeresidual propan-2-ol and water, leaving crude title compound as a palegreen oil (4.53 g).

EXAMPLE 4(2R*,4aR*,8aS*)-Octahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazine(a) Direct reduction

A suspension of lithium aluminium hydride (2.1 g) in dry ether (50 cm³)was treated over 2 hr with a solution of crude lactam product of Example3 (7.65 g) in dry ether (100 cm³). The mixture was heated to reflux for24 hr, cooled, and treated with saturated potassium sodium tartratesolution (300 cm³). The phases were separated and the aqueous phase wasextracted with ether (3×50 cm³). The combined ether solutions were dried(Na₂ SO₄) and evaporated, leaving impure title compound base as a paleyellow oil (6.97 g).

The crude base (6.71 g) was converted to its hydrogen oxalate salt inethyl acetate, and recrystallised from ethyl acetate-methanol(charcoal). The crystals were collected and washed with ethyl acetate(2×25 cm³), then ether (25 cm³) and dried, giving the title compoundhydrogen oxalate as colourless crystals (4.65 g) m.p. 204°-6° (decomp.with gas evolution).

Found: C, 62.4; H, 7.8; N, 3.7. C₁₇ H₂₅ NO₂.C₂ H₂ O₄ requires C, 62.45;H, 7.45; N, 3.8%.

(b) Alternative process

Crude lactam product of Example 3 (4.26 g) in ether (100 cm³) wastreated with solid lithium aluminium hydride (0.56 g), at roomtemperature. The mixture was heated to reflux for 3 hr and then kept atroom temperature overnight (22 hr.). Saturated potassium sodium tartratesolution (50 cm³) was added, stirred 1 hr, and the phases wereseparated. The aqueous phase was extracted with ether (3×30 cm³). Theextracts were dried (Na₂ SO₄) and evaporated, leaving impure(4aR*,8aS*)-4a,5,6,7,8,8a-hexahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-4H-benzoxazineas a colourless oil (3.5 g) which rapidly turned yellow-brown onexposure to air.

The impure product (1.0243 g) was hydrogenated in ethanol (30 cm³) over5% Pd/C (100 mg) at atmospheric pressure and 15°-16°. Total absorption75 cm³ (3.07 mmol, 82%) after 280 min. The catalyst was removed, washedwith ethanol, and the filtrate and washings were evaporated underreduced pressure, leaving a yellow oil (1.07 g).

The oil was chromatographed over silica gel to give the title compoundas a colourless oil (0.75 g) shown spectroscopically and by mixedmelting point of the oxalate salts to be identical to material preparedby the direct route (a).

EXAMPLE 53-[(2R*,4aR*,8aS*)-octahydro-2,4-dimethyl-2H-benzoxazin-8a-yl]phenol

(2R*,4aR*,8aS*)-Octahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazinehydrogen oxalate (1 g) was slurried in dry toluene (10 cm³) under drynitrogen. Diisobutylaluminium hydride (20% in toluene, 1.2 M, 18.5 cm³)was added cautiously and the mixture was then heated to reflux for 22 h.The cooled mixture was treated very cautiously with saturated Rochellesalt solution (100 cm³), followed by ether (50 cm³). The mixture wasstirred to dissolve aluminium salts and the phases were then separated.The aqueous phase was extracted repeatedly with ether (8×30 cm³) andthen with chloroform (50 cm³). The organic phases were combined, dried(Na₂ SO₄) and evaporated, giving impure product as an oil which rapidlycrystallised (0.87 g). The solid was converted to its hydrochloride saltand crystallised from ethanol-methanol giving the title compoundhydrochloride as colourless crystals (0.47 g) m.p. 285°-8° (decomp.above 270°).

Found: C, 64.6; H, 8.1; N, 4.55. C₁₆ H₂₃ NO₂.HCl requires C, 64.5; H,8.1; N, 4.7%.

EXAMPLE 6 (1R*,2R*)-1-(3-Methoxyphenyl)-2-methylaminocyclohexanol and(1R*,2S*)-1-(3-methoxyphenyl)-2-methylaminocyclohexanol

2-Methylaminocyclohexanone hydrochloride (L. Bernardi, C. Fuganti, andD. Ghiringhelli, Gazz. Chim. Ital. 1968, 98, 836-847) (20 g) was addedslowly in small portions to a stirred refluxing solution of3-methoxyphenyl magnesium bromide [prepared from magnesium (16 g) and3-bromoanisole (120 g)] in dry ether (350 cm³) and T.H.F. (200 cm³). Themixture was heated under reflux for 17 hr. and was then cooled andpoured on to ice (330 g) containing concentrated hydrochloric acid (60cm³). The phases were separated and the ether phase was extracted with 2N-hydrochloric acid (50 cm³). The combined acid solutions were extractedwith ether (100 cm³) and were then concentrated under reduced pressureto remove T.H.F. The residual aqueous solution was made alkaline withconcentrated ammonia and the product was extracted into ether (5×250cm³). The combined, dried (Na₂ SO₄)extracts were evaporated leaving anoil, which was re-evaporated with toluene (50 cm³) to give the impureamino alcohol mixture as a yellow oil (27.55 g). On standing the oilbecame partially crystalline and was separated by filtration into aliquid phase (18.03 g) and a pasty solid (8.52 g). The pasty solid wasshown by IR, NMR and GLC to consist largely of the (1R*,2S*) isomer,with the (1R*,2R*) isomer as minor component. The liquid phase wasshown, by IR, NMR and GLC to consist of ˜85% (1R*,2R*) isomer, nodetectable (1R*,2S*) isomer, and 10-15% of1-(3-methoxyphenyl)-2-methylaminocyclohexene. The 1R*,2R* isomer wasconverted to its hydrochloride and recrystallised from ethylacetate-methanol giving the title compound hydrochloride as colourlessprisms, m.p. 217°-220° C.

Found: C, 61.6; H, 8.3; N, 4.9. C₁₄ H₂₁ NO₂.HCl requires C, 61.9; H,8.2; N, 5.15%.

EXAMPLE 7 (2R*,4aR*,8aR*) and(2R*,4aS*,8aS*)-hexahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazin-3(4H)-one

Crude (1R*,2R*)-1-(3-methoxyphenyl)-2-methylaminocyclohexanol (4.7 g,from Example 6) was dissolved in dichloromethane (50 cm³) containingtriethylamine (2.8 cm³, 2.02 g). The solution was cooled to 10° in abath of cold water and treated dropwise with 2-bromopropionyl bromide(2.33 cm³, 4.32 g). The mixture was stirred for 1 hr. while cooling andwas then concentrated under reduced pressure to an oily solid. This waspartitioned between N hydrochloric acid (50 cm³) and ether (50 cm³), andthe aqueous phase was extracted with further ether (3×20 cm³). The etherextracts were dried (Na₂ SO₄) and evaporated, leaving crude(1R*,2R*)-2-(2-bromopropionyl-N-methylamino)-1-(3-methoxyphenyl)cyclohexanolas a yellow oil (7.7 g).

The crude, oily bromoamide (7.7 g) was dissolved in warm propan-2-ol (50cm³) and treated with vigorous stirring with 10 N aqueous sodiumhydroxide (4 cm³). The mixture was kept at room temperature overnightand was then concentrated under reduced pressure. The residue wasre-evaporated with toluene (50 cm³) to remove propan-2-ol, and theresidue was diluted with water (50 cm³). The product was extracted intoether (4×25 cm³) and the extracts were dried (Na₂ SO₄) and evaporated,leaving a crude mixture of the title diastereoisomers as a brown oil(5.42 g).

EXAMPLE 8 (2R*,4aR*,8aR*) and(2R*,4aS*,8aS*)-octahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazines

Lithium aluminium hydride (1.8 g) was stirred and heated to reflux indry ether (50 cm³) for 5 min. before the slow addition of the mixture of(2R*,4aR*,8aR*) and (2R*,4aS*,8aS*) lactam products of Example 7 (5.42g) in dry ether (100 cm³) over 30 min. The mixture was heated to refluxfor 4 hr. and was then cooled and treated with saturated Rochelle saltsolution (100 cm³) and water (25 cm³). The phases were separated and theaqueous phase was extracted with further ether. The combined etherphases were dried (Na₂ SO₄) and evaporated, leaving a crude mixture ofthe title benzoxazines as an oil (4.47 g). The mixture was separated bychromatography over silica gel giving the title compound (2R*,4aR*,8aR*)isomer (2.53 g) which crystallised on standing and the title compound(2R*,4aS*8aS*) isomer (1.63 g) as an oil.

EXAMPLE 9(4aR*,8aS*)-Hexahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazin-3(3H)-one

The product of Example 1 (4.7 g) in dichloromethane (60 cm³) containingtriethylamine (2.8 cm³), was treated with chloroacetyl chloride (1.6cm³) dropwise with stirring and external cooling. The mixture wasstirred for a further 3/4 hr. and was then evaporated. The residue wasdissolved in 2 N sulphuric acid (30 cm³) and the neutral product wasextracted into ether. The ether extracts were washed with 2 N sulphuricacid, water and saturated brine and dried (Na₂ SO₄). Removal of thesolvent left crude(1R*,2R*)-2-(2-chloroacetyl-N-methylamino)-1-(3-methoxyphenyl)cyclohexanolas an oil (6.44 g).

The crude amide (6.03 g) was dissolved in warm propan-2-ol (60 cm³) andtreated with 10 N sodium hydroxide solution (5.8 cm³). The mixture wasstirred vigorously at room temperature for 1 hr. The solvent was removedand the aqueous residue was diluted with water (30 cm³). The cyclisedproduct was extracted into ether and the combined extracts were washedwith saturated brine and dried (Na₂ SO₄). Removal of the solvent leftcrude title product as an oil (5.26 g).

EXAMPLE 10(2R*,4aS*,8aR*)-Hexahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazin-3(4H)-one

A solution of crude(4aR*,8aS*)-hexahydro-8a-(3-methoxyphenyl)-4-methyl-2H-benzoxazin-3(4H)-one(1.63 g) in dry THF (5 cm³) was added dropwise under nitrogen to astirred solution of lithium di-isopropylamide [from n-butyllithium 1.55M in hexane (3.75 cm³) and di-isopropylamine (0.82 cm³, 0.59 g) in THF(2 cm³)] at 10°. The mixture was stirred for 15 mins at 10° and was thentreated with methyl iodide (1 cm³, 2.28 g). Stirring was continued for afurther 15 min. then the mixture was poured into 0.5 N hydrochloric acid(25 cm³) and concentrated under reduced pressure to remove THF andexcess methyl iodide. The product was then extracted into ether and theextracts were dried (Na₂ SO₄) and evaporated, leaving a yellow gum (1.63g) shown by IR, NMR and GLC to contain ˜85% title compound, and about 5%of the (2R*,4aR*,8aS*) isomer.

EXAMPLE 11(2R*,4aR*,8aS*)-2-Ethyl-hexahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazin-3(4H)-one

The product of Example 1 (2.35 g) in dichloromethane (25 cm³) containingtriethylamine (1.4 cm³) was treated dropwise with 2-bromobutyrylchloride (1.2 cm³). The mixture was then allowed to cool to roomtemperature over 21/2 hr. The solvent was removed and the semi-solidresidue was partitioned between ether (50 cm³) and N hydrochloric acid(50 cm³). The aqueous phase was extracted with further ether and thecombined ether extracts were dried (Na₂ SO₄) and evaporated, leaving thebromo-amide as an oil (3.73 g).

The crude bromo-amide (3.65 g) in warm propan-2-ol (30 cm³) was treatedwith 10 N sodium hydroxide solution (3 cm³) with vigorous stirring for 3hr. The solvent was removed and the aqueous residue was diluted withwater (30 cm³). The product was extracted into ether, dried (Na₂ SO₄),and the solvent removed, leaving the crude title compound as an oil(2.55 g).

EXAMPLE 12(2R*,4aR*,8aR*)-3-(Octahydro-2,4-dimethyl-2H-1,4-benzoxazin-8a-yl)phenol

The (2R*,4aR*,8aR*) product of Example 8 (2.24 g) in dry toluene (22cm³) was treated under argon at room temperature withdi-isobutylaluminium hydride (25° wt % in toluene, 11 cm³) and themixture was then heated to reflux for 22 hr. The cooled solution wastreated with saturated potassium sodium tartrate solution (25 cm³),ether (20 cm³), and water (10 cm³) and stirred until the aluminium saltshad dissolved. The mixture was separated. The aqueous phase wasextracted with ether and the combined organic solutions were dried (Na₂SO₄) and evaporated, leaving the phenol as a solid (2.11 g), m.p.188°-193°. The solid was converted to its hydrochloride salt in ethylacetate-ether and the salt was recrystallised from ethylacetate-methanol, giving the title compound hydrochloride as colourlesscrystals (2.17 g), m.p. 246°-8° (decomp. rapidly above 200°).

Found: C, 64.6; H, 8.4; N, 4.5. C₁₆ H₂₃ NO₂.HCl requires C, 64.5; H,8.1; N, 4.7%.

EXAMPLE 13(2R*,4aS*,8aS)-3-(Octahydro-2,4-dimethyl-2H-1,4-benzoxazin-8a-yl)phenol

The (2R*,4aS*,8aS*) product of Example 8 (1.4 g) in toluene (15 cm³) wastreated under argon at room temperature with di-isobutylaluminiumhydride (25 wt % in toluene, 6.7 cm³) and the mixture was heated toreflux for 22 hr. The cooled solution was treated cautiously withsaturated potassium sodium tartrate solution (25 cm³), ether (20 cm³)and water (10 cm³) and stirred until aluminium salts had dissolved. Themixture was separated. The aqueous phase was extracted with ether andthe combined organic solutions were dried (Na₂ SO₄) and evaporated,leaving the phenol as a colourless oil (1.46 g). The oil was convertedto its hydrochloride salt in ethyl acetate-ether and the salt wascrystallised from ethyl acetate-methanol giving the title compoundhydrochloride as colourless crystals (1.2 g), m.p. 246°-8° (decomp.rapidly above 200°).

Found: C, 64.4; H, 8.3; N, 4.3. C₁₆ H₂₃ NO₂.HCl requires: C, 64.5; H,8.1; N, 4.7%.

EXAMPLE 14(4aR*,8aS*)-Octahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazine(a) using lithium aluminium hydride

The crude product of Example 9 (1.02 g) in dry ether (50 cm³) was addeddropwise over 3/4 hr. to a refluxing suspension of lithium aluminiumhydride (0.35 g) in dry ether (25 cm³). After 6 hr. at reflux, themixture was cooled and treated dropwise with saturated Rochelle saltsolution (100 cm³) and the mixture was stirred until the solids haddissolved. The phases were separated and the aqueous phase was extractedwith ether. The combined organic solutions were dried (Na₂ SO₄) andevaporated, leaving crude title compound as a clear oil (0.93 g).

(b) using borane-T.H.F. complex

The crude product of Example 9 (1.02 g) in dry T.H.F. (10 cm³) wastreated at room temperature under nitrogen with borane-T.H.F. complex (1M in T.H.F., 10 cm³). The mixture was kept at room temperature for 24hr. under nitrogen, and was then added to a stirred mixture of hydrogenperoxide (20 vol, ˜6% w/v, 25 cm³) and 2 N sodium hydroxide (5 cm³).After 1/2 hr. sodium sulphite was added until no peroxide was detectedby starch-iodide paper, and the phases were separated. The aqueous phasewas extracted with ether and the combined organic phases were dried (Na₂SO₄) and evaporated. The residue was re-evaporated with toluene (50cm³). The almost colourless oily borane adduct (1.1 g) was kept in anopen flask for 4 weeks to hydrolyse with atmospheric moisture, giving anopaque, solid mass. The mass was partitioned between N sodium hydroxide(15 cm³) and ether (15 cm³) and the aqueous phase was extracted withfurther ether. The ether phases were dried (NaSO₄) and evaporated,giving the title compound as a clear, colourless oil (0.74 g).

EXAMPLE 15(4aR*,8aS*)-3-(Octahydro-4-methyl-2H-1,4-benzoxazin-8a-yl)phenol

The crude product of Example 14 (1.34 g) in dry toluene (20 cm³) wastreated at room temperature under nitrogen with di-isobutylaluminiumhydride (1.2 M in toluene, 8.6 cm³). The solution was then heated toreflux for 22 hr. The cooled solution was treated with saturatedRochelle salt solution (50 cm³), then water (12.5 cm³) and ether (15cm³). The resulting suspension was stirred until the aluminium salts haddissolved. The mixture was separated. The aqueous phase was extractedwith chloroform (4×30 cm³) and the combined organic phases were dried(Na₂ SO₄) and evaporated, leaving a pink solid (1.16 g). This wasconverted to its hydrochloride salt in ethyl acetate-methanol-ether andthe solid product was washed with ether giving a crystalline solid (0.69g) of the title compound as the hydrochloride two thirds hydrate, m.p.250°-2° (decomp.).

Found: C, 60.9; H, 7.8; N, 4.5. C₁₅ H₂₁ NO₂.HCl.2/3 H₂ O requires C,60.9; H, 7.95; N, 4.7%.

EXAMPLE 16(2R*,4aS*,8aR*)-Octahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazine

The crude product of Example 10 (1.36 g) in dry ether (25 cm³) was addeddropwise to a stirred, refluxing suspension of lithium aluminium hydride(0.45 g) in dry ether (10 cm³). The mixture was heated to reflux for 6hr. and was then allowed to cool. Saturated Rochelle salt solution (50cm³) was added and the mixture was stirred to dissolve aluminium salts.The phases were separated and the aqueous phase was extracted withfurther ether. The extracts were dried (Na₂ SO₄) and evaporated, leavingthe title product as an oil (1.27 g). The crude title base (1.1 g) wasconverted in ethyl acetate to its hydrogen oxalate salt, which wasrecrystallised from ethyl acetate-methanol giving crystals (0.73 g),m.p. 213°-5° (decomp.).

Found: C, 62.3; H, 7.5; N, 3.6. C₁₇ H₂₅ NO₂.C₂ H₂ O₄ requires C, 62.45;H, 7.45; N, 3.8%.

EXAMPLE 17(2R*,4aS*,8aR*)-3-(Octahydro-2,4-dimethyl-2H-1,4-benzoxazin-8a-yl)phenol

The oxalate salt from Example 16 (0.73 g) was slurried in dry toluene(7.5 cm³) under nitrogen and treated with di-isobutylaluminium hydride(25% w/w in toluene 8 cm³) at room temperature. The mixture was heatedto reflux for 21 hr. then further di-isobutylaluminium hydride solution(4 cm³) was added in 2 portions. Heating was continued for a further 28hr, then the mixture was allowed to cool. The solution was treated withsaturated Rochelle salt solution (50 cm³), water (10 cm³) and ether (20cm³) and stirred 1/2 hr. to dissolve the aluminium salts. The mixturewas separated and the aqueous phase was extracted with ether. Thecombined organic phases were dried (Na₂ SO₄) and evaporated, leavingcrude title compound as a solid (0.59 g). The solid was converted to itshydrochloride in ethyl acetate-ether and the salt was recrystallisedfrom ethyl acetate-methanol as colourless crystals (0.30 g, m.p.291°-291.5° (decomp. before melting).

Found: C, 64.3; H, 8.2; N, 4.6. C₁₆ H₂₃ NO₂.HCl requires C, 64.5; H,8.1, N, 4.7%.

EXAMPLE 18(2R*,4aR*,8aS*)-2-Ethyl-octahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazine

A warm suspension of lithium aluminium hydride (0.8 g) in dry ether (20cm³) was stirred for 5 min. before the dropwise addition of the crudeproduct of Example 11 (2.55 g) dissolved in ether (50 cm³) over 15 min.The mixture was then heated to reflux for 6 hr. The cooled solution wastreated with saturated Rochelle salt solution (75 cm³) and water (25cm³) and stirred until the aluminium salts had dissolved. The phaseswere separated and the aqueous phase was extracted with ether. Thecombined organic solutions were dried (Na₂ SO₄) and evaporated, leavingan oil (2.29 g).

The crude oil (2.07 g) in ethyl acetate was filtered into a warmsolution of oxalic acid dihydrate (0.9 g) in ethyl acetate. Thedeposited crystals of the oxalate salt (1.74 g) were recrystallised fromethyl acetate-methanol to give pure title compound as the hydrogenoxalate (1.26 g), m.p. 207°-9° (decomp).

Found: C, 63.6; H, 7.8; N, 3.5. C₁₈ H₂₇ NO₂.C₂ H₂ O₄ requires C, 63.3;H, 7.7; N, 3.7%.

EXAMPLE 19 (2R*,4aR*,8aS*)-3-(2-Ethyloctahydro-4-methyl-2H-1,4-benzoxazin-8a-yl)phenol

The hydrogen oxalate product from Example 18 (1.09 g) was slurried indry toluene (10 cm³) under nitrogen and was treated withdi-isobutylaluminium hydride (1.2 M in toluene, 14.4 cm³, 17.3 mmol).The solution was heated to reflux under nitrogen for 22 hr. The cooledsolution was treated with saturated Rochelle salt solution (50 cm³),followed by ether (15 cm³) and water (12.5 cm³). The resultingsuspension was stirred until the aluminium salts had dissolved, then thephases were separated and the aqueous phase was extracted with ether andchloroform. The combined organic phases were dried (Na₂ SO₄) andevaporated, leaving the crude base as large prisms (0.9 g). The materialwas converted to its hydrochloride salt which was recrystallised fromethyl acetate-methanol giving the title compound hydrochloride ascolourless crystals (0.56 g), m.p. 233°-5° (decomp).

Found: C, 65.4; H, 9.0; N, 4.15. C₁₇ H₂₅ NO₂.HCl requires C, 65.5; H,8.4: N, 4.5%.

EXAMPLE 20 (2R*,4aS*,8aS*) and(2R*,4aR*,8aR*)-2-Ethylhexahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazin-3(4H)-one

The (1R*,2R*) product of Example 6 (4.7 g) in dichloromethane (50 cm³)containing triethylamine (2.8 cm³) was treated, with cooling, dropwisewith 2-bromobutyrylchloride (2.5 cm³). The solution was allowed to stand1 hr. The solvent was removed and the residue was partitioned betweenether (50 cm³) and N hydrochloric acid (50 cm³). The combined ethersolutions were dried (Na₂ SO₄) and evaporated, leaving the crudebromoamide as an oil (8.09 g).

The oily bromoamide (8.0 g) was treated in warm propan-2-ol (50 cm³)with 10 N sodium hydroxide solution (4 cm³) with vigorous stirring for 1hr. The mixture was left overnight at room temperature and was thenconcentrated. The aqueous residue was diluted with water (50 cm³) andthe lactam product was extracted into ether, dried (Na₂ SO₄) andevaporated, giving crude title compound as oil (6.02 g), containing a60:40 mixture of isomers.

EXAMPLE 21 (2R*,4aR*,8aR*) and(2R*,4aS*,8aS*)-2-Ethyloctahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazines

A suspension of lithium aluminium hydride (1.9 g) in dry ether (50 cm³)was heated to reflux for 5 min. before the slow addition of the mixedlactams products of Example 20 (6.02 g) in ether (100 cm³) over 1/2 hr.The mixture was heated to reflux for 4 hr., cooled, treated withsaturated Rochelle salt solution (100 cm³) and water (25 cm³), stirreduntil aluminium salts had dissolved, and separated. The aqueous phasewas extracted with ether and the combined ether solutions were dried(Na₂ SO₄) and evaporated, giving a mixture of title compounds as oil(5.04 g).

The mixture (4.9 g) was separated by chromatography over silica gelgiving almost pure (2R*,4aR*,8aR*) isomer (2.27 g). The (2R*,4aS*,8aS*)isomer was obtained free from the (2R*,4aR*,8aR*) isomer but containingtraces of other, minor impurities.

EXAMPLE 22(2R*,4aR*,8aR*)-3-(2-Ethyloctahydro-4-methyl-2H-1,4-benzoxazin-8a-yl)phenol

Purified (2R*,4aR*,8aR*) isomer from Example 21 (99% pure by GLC) (2.04g) in toluene (20 cm³) was treated at room temperature under nitrogenwith di-isobutylaluminium hydride (25% w/w in toluene, 9.5 cm³). Themixture was heated to reflux under nitrogen for 22 hr, cooled, treatedwith saturated Rochelle salt solution (50 cm³) and ether (10 cm³). Themixture was stirred to dissolve the aluminium salts, separated, and theaqueous phase was extracted with ether (3×50 cm³). The combined organicphases were dried (Na₂ SO₄) and evaporated, leaving crude title compoundas a solid (1.85 g). The solid (1.77 g) was dissolved in ethyl acetateand added to a solution of oxalic acid dihydrate (0.81 g) in ethylacetate. The solid deposited was recrystallised from ethylacetate-methanol to give title compound hydrogen oxalate as needles(1.82 g), m.p. 186.5°-188° (decomp).

Found: C, 62.5; H, 7.55; N, 3.6. C₁₇ H₂₅ NO₂.C₂ H₂ O₄ requires C, 62.45;H, 7.45; N, 3.8%.

EXAMPLE 23(2R*,4aS*,8aS*)-3-(2-Ethyloctahydro-4-methyl-2H-1,4-benzoxazin-8a-yl)phenol

Partially purified (2R*,4aS*,8aS*) product from Example 21 [87.8%2R*,4aS*,8aS*; 4.5% 2R*,4aR*,8aR* by GLC] (1.48 g) in toluene (15 cm³)was treated under nitrogen at room temperature with di-isobutylaluminiumhydride (25% w/w in toluene, 7 cm³). The mixture was then heated toreflux for 17 hr, cooled, and treated with saturated Rochelle saltsolution (50 cm³) and water (10 cm³). The mixture was stirred until thealuminium salts had dissolved and was separated. The aqueous phase wasextracted with ether. The organic phases were dried (Na₂ SO₄) andevaporated, giving crude title compound as an oil (1.46 g). The crudebase (1.25 g) was dissolved in ethyl acetate and added to a solution ofoxalic acid dihydrate (0.57 g) in ethyl acetate. The solid deposited wasrecrystallised from ethyl acetate-methanol giving the title compound asthe hydrogen oxalate (1.07 g), m.p. 208°-210° (decomp).

Found: C, 62.6; H, 7.7; N, 3.6. C₁₇ H₂₅ NO₂.C₂ H₂ O₄ requires C, 62.45;H, 7.45; N, 3.8%.

EXAMPLE 24 (1R*,2S*)-1-(3-Methoxyphenyl)-2-methylamino-1-cyclopentanol

Crude 1-(3-methoxyphenyl)cyclopentene oxide (prepared according to themethod of Ger. Offen. No. 2,942,644) is treated with ethanolicmethylamine solution by the method of Example 1(b) above to give thetitle compound.

EXAMPLE 25(1R*,2S*)-2-(2-bromopropion-N-methylamido)-1-(3-methoxyphenyl)-1-cyclopentanol

The product of Example 24 is treated with 2-bromopropionyl bromide bythe procedure of Example 2 to give the crude title compound.

EXAMPLE 264a,6,7,7a-Tetrahydro-7a-(3-methoxyphenyl)-2,4-dimethyl-2H,5H-cyclopent[b][1,4]-oxazin-3(4H)-one

Crude bromoamide product of Example 25 is treated with sodium hydroxideby the method of Example 3 to give the title compound.

EXAMPLE 27Hexahydro-7a-(3-methoxyphenyl)-2,4-dimethyl-2H,5H-cyclopent[b][1,4]oxazine

The product of Example 26 is reduced by the procedure of Example 4a togive the title compound.

EXAMPLE 28(1R*,2S*)-2-(2-Bromononan-N-methylamide)-1-(3-methoxyphenyl)-1-cyclohexanol

The product of Example 1 is treated with 2-bromononanoyl chloride by themethod of Example 2 to provide the title compound.

EXAMPLE 29Hexahydro-2-heptyl-8a-(3-methoxyphenyl)-4-methyl-2H-[1,4]-benzoxazin-3(4H)-one

The crude product of Example 28 is treated by the method of Example 2 togive the title product.

EXAMPLE 30Octahydro-2-heptyl-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazine

The product of Example 29 is reduced by the procedure of Example 9a togive the title compound.

We claim:
 1. A compound selected from the group consisting of amorpholine derivative of formula (I) ##STR12## and a pharmaceuticallyacceptable acid addition salt thereof, wherein n represents 1,2 or 3, R²and R³ are each hydrogen or alkyl of 1 to 10 carbon atoms, R⁴ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl,2-tetrahydrofurylmethyl or cyclo(lower)alkylmethyl and OR⁵ is hydroxy,acyloxy or lower alkoxy.
 2. A compound as claimed in claim 1 wherein nis
 2. 3. A compound as claimed in claim 1 which isoctahydro-8a-(3-methoxyphenyl)-2,4-dimethyl-2H-1,4-benzoxazine or apharmaceutically acceptable acid addition salt thereof.
 4. A compound asclaimed in claim 1 which is3-(octahydro-2,4-dimethyl-2H-benzoxazin-8a-yl)phenol or apharmaceutically acceptable acid addition salt thereof.
 5. A compound asclaimed in claim 1 which is3-[(2R*,4aR*,8aS*)-octahydro-2,4-dimethyl-2H-benzoxazin-8a-yl]phenol ora pharmaceutically acceptable acid addition salt thereof.
 6. A compoundas claimed in claim 1 which isoctahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazine or apharmaceutically acceptable acid addition salt thereof.
 7. A compound asclaimed in claim 1 which is3-(octahydro-1-methyl-2H-1,4-benzoxazin-8a-yl)phenol or apharmaceutically acceptable acid addition salt thereof.
 8. A compound asclaimed in claim 1 which is2-ethyloctahydro-8a-(3-methoxyphenyl)-4-methyl-2H-1,4-benzoxazine or apharmaceutically acceptable acid addition salt thereof.
 9. A compound asclaimed in claim 1 which is3-(2-ethyloctahydro-4-methyl-2H-1,4-benzoxazin-8a-yl)phenol or apharmaceutically acceptable acid addition salt thereof.
 10. Apharmaceutical composition comprising a compound selected from the groupconsisting of a morpholine derivative of formula (I) ##STR13## and apharmaceutically acceptable acid addition salt thereof, wherein nrepresents 1,2 or 3, R² and R³ are each hydrogen or alkyl of 1 to 10carbon atoms, R⁴ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cyclo(lower)alkylmethyl andOR⁵ is hydroxy or acyloxy in association with a pharmaceuticallyacceptable carrier.
 11. A method of treating a mammal in need of ananalgesic or opiate antagonist which comprises administering to saidmammal an analgesically or opiate antagonistically effective amount of acompound selected from the group consisting of a morpholine derivativeof formula (I) ##STR14## and a pharmaceutically acceptable acid additionsalt thereof, wherein n represents 1, 2 or 3, R² and R³ are eachhydrogen or alkyl of 1 to 10 carbon atoms, R⁴ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethylor cyclo(lower)alkylmethyl and OR⁵ is hydroxy or acyloxy.